PROJECT SUMMARY for the PROVE Trial More than 65% of people with lower extremity peripheral artery disease (PAD) are overweight or obese. People with PAD who are overweight or obese have greater functional impairment and faster functional decline than normal weight people with PAD. Walking exercise is first line therapy to improve functional performance in PAD. However, our observational longitudinal data show that overweight and obese PAD participants who combined weight loss with walking exercise had less functional decline than those who walked for exercise but did not lose weight. Therefore, we hypothesize that among people with PAD who are overweight or obese, a weight loss intervention combined with exercise (WL+EX) will improve walking ability more than EX alone. However, effects of intentional weight loss in overweight/obese people with PAD are unknown and may not be beneficial if weight loss exacerbates PAD-related sarcopenia. Behavior change that achieves sustained WL is challenging in older obese people with chronic disease. Therefore, among people with PAD and BMI>28 kg/m2, we will test the hypothesis that WL+EX achieves greater improvement in functional performance than EX alone. Our innovative weight loss intervention uses a group mediated cognitive behavioral framework, connective mobile technology, remote monitoring by a coach, and a calorie restricted DASH-derived OMNIHeart diet. In a seven week pilot study, our intervention achieved mean weight loss of 5.6 pounds and improved the 6-minute walk by 64.1 meters in eight PAD participants with BMI> 28 kg/m2. Preclinical evidence shows that obesity is associated with impaired limb perfusion. Human evidence shows that obesity is associated with reduced skeletal muscle mitochondrial biogenesis and activity. These obesity related changes exacerbate the pathophysiology of PAD. Therefore, we hypothesize that weight loss will improve walking ability in part by improving calf perfusion, and increasing calf mitochondrial activity. We will randomize 212 participants with PAD and BMI > 28 kg/m2 to one of two groups for 12 months: WL+ EX vs. EX alone. Participants will be randomized from Northwestern University, Tulane University, and the U. of Minnesota. Our primary outcome is change in six-minute walk distance at 12-month follow-up. Secondary outcomes are change in 6-minute walk distance at 6-month follow-up and change in exercise adherence, physical activity, patient-reported walking ability (measured by the Walking Impairment Questionnaire), and quality of life (measured by the SF12 Physical Component Score) at 12-month follow-up. Tertiary outcomes include MRI measured calf perfusion, MRI-measured calf muscle quantity and fat abundance, and diet quality. We will perform calf muscle biopsies in 50 participants to measure mitochondrial biogenesis and activity, capillary density, inflammation, and senescent cell abundance. If our hypotheses are correct, the PROVE Trial will have a major public health impact by preventing functional decline and mobility loss in the large and growing number of people with PAD who are overweight or obese.